: Description The longterm goal of this grant application is to develop a defective HSV-1 vector system that can be used for human gene therapy. HSV-1 vectors are particularly attractive for gene therapy of neurodegenerative diseases in the aging brain, such as Parkinson disease, but HSV-1 vectors may also be applicable to other neurological disorders. The investigators have shown that HSV-1 vectors that express TH can direct long-term biochemical and behavioral recovery in a rodent model of PD. Additionally, they recently developed a helper virus-free packaging system for HSV-1 vectors that addresses many of the current concerns about the vector system. In this application, the investigators describe experiments to test two hypotheses: The first hypothesis is that a further reduction in side effects of the vector system can be obtained by mutating specific components of the HSV-1 particle. The second hypothesis is that improved stability of long-term expression and improved accuracy of cell type-specific expression can be obtained by further reducing specific side effects of the vector system and by improving the structure of the vectors. These studies are designed to develop HSV-1 vector systems that cause minimal side effects and support stable long-term expression. Achieving these goals would represent meaningful progress towards the development of a HSV-1 vector system that might potentially be considered for human gene therapy.